In disorders such as rheumatoid arthritis and scleroderma, connective tissue cells isolated from lesional tissue display and abnormal phenotype; furthermore this phenotype is propagable through multiple generations of in vitro culture. The present proposal will use an in vitro model to study how short-term transient exposure of dermal and synovial fibroblasts to products of stimulated lymphocytes and monocytes might lead to metabolic abnormalities that persist in culture. Preliminary data indicate that short term exposure of dermal fibroblasts to products of mononuclear cells results in populations that show enhanced proliferation and stimulated prostaglandin E2 (PGE2) synthesis compared to control populations; the abnormal metabolic phenotype is propagable through multiple cell generations in culture. These studies will be extended to examine synthesis of collagen, collagenase and tissue factor in cell populations briefly exposed to supernates of activated mononuclear cell cultures. To determine whether permanent alterations in fibroblast populations resulting from exposure to mononuclear cell factors arise as a consequence of immune-mediated clonal selection, cloned dermal and synovial fibroblasts will be studied. Cloned populations will be examined for metabolic heterogeneity and for responses to mononuclear cell derived factors. Two or more clones will be cocultured for short intervals in the presence of mononuclear cell supernates to determine whether there is a clonal selection. Alternative mechanisms for the persistent effect on fibroblasts of transient exposure to mononuclear cell products will also be explored.